1. Field of the Invention
The present invention relates to the field of therapeutics and compositions for use in the treatment of neurodegenerative tauopathies.
2. Description of the Related Art
Tauopathies are a group of neurodegenerative diseases with the pathological hallmark of abnormal intracellular aggregates of the microtubule-associated tau protein in the form of fibrils/filaments/fibers in the brain. These tauopathies include diseases such as Alzheimer's disease, Amyotrophic lateral sclerosis/parkinsonism-dementia complex, Argyrophilic grain dementia, Corticobasal degeneration, Creutzfeldt-Jakob disease, Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Frontotemporal dementia with parkinsonism linked to chromosome 17, Gerstmann-Str{umlaut over ( )}aussler-Scheinker disease, Hallervorden-Spatz disease, Myotonic dystrophy, Niemann-Pick disease type C, Non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, Postencephalitic parkinsonism, Prion protein cerebral amyloid angiopathy, Progressive subcortical gliosis, Progressive supranuclear palsy, Subacute sclerosing panencephalitis, Tangle only dementia (Lee et al., 2001). While tauopathies have diverse phenotypes and clinical characteristics, they all share in common the presence of neurofibrillary tangles (NFT) of insoluble, hyperphosphosylated tau in the form of fibrils/filaments/fibers, e.g., twisted, straight or paired helical.
Tau protein is a microtubule-associated protein encoded by the MAPT gene located in chromosome 17, and it exists in neurons as a soluble phosphosylated protein involved with stabilizing and promoting the polymerization of microtubules. Abnormal hyperphosphosylation of tau, as seen in neurofibrillary tangles, decreases tau protein's microtubule binding ability and inhibits its ability to promote microtubule assembly.
Therapeutic strategies directed to tauopathies, as reviewed in Pritchard et al. (2011), include (i) small molecule inhibitors of tau aggregation such as the phenothiazine compound methylene blue and the N3 benzothiazole derivative, (ii) microtubule stabilizing agents such as taxol (paclitaxel), (iii) tau immunotherapy, (iv) autophagy activators, such as rapamycin, to effect clearance of insoluble and pathological tau fibrils, and (v) antioxidant molecules, such as vitamins C and E, glutathione, ubiquinone, and a ubiquinone derivative MitoQ.
Filamentous bacteriophages are a group of structurally related viruses which contain a circular single-stranded DNA genome. Filamentous bacteriophages are neither lytic nor lysogenic and they do not kill their host during productive infection. The phages that infect Escherichia coli containing an F factor are collectively referred to as Ff bacteriophages. These bacteriophage do not infect eukaryotice cells, including mammalian cells.
The filamentous bacteriophages are flexible rods about 1 to 2 microns long (for Ff bacteriophage, only about 1 micron in length) and 6 nm in diameter, with a helical shell of protein subunits surrounding a single stranded, circular DNA genomic core. For filamentous bacteriophage in the Ff family (those filamentous bacteriophage, M13, fd, and f1, that infect E. coli through the F-pilus), the two main coat proteins, protein pIII and the major coat protein pVIII, differ in the number of copies of the displayed protein. While pIII is presented in 3-5 copies, pVIII is found in ˜3000 copies. The approximately 50-residue major coat protein pVIII subunit is largely α-helical and the axis of the α-helix makes a small angle with the axis of the virion. The protein shell can be considered in three sections: the outer surface, occupied by the N-terminal region of the subunit, rich in acidic residues that interact with the surrounding solvent and give the virion a low isoelectric point; the interior of the shell, including a 19-residue stretch of apolar side-chains, where protein subunits interact mainly with each other; and the inner surface, occupied by the C-terminal region of the subunit, rich in basic residues that interact with the DNA core.
Filamentous bacteriophages of the Ff family (especially M13) have been exploited as peptide display systems using two structural proteins of filamentous bacteriophage, the pIII (p3) protein and the pVIII protein, as display scaffolds for the peptides. Peptide epitopes have been displayed on filamentous phage for use in active immunization.
It has previously been demonstrated that filamentous bacteriophage, in particular M13, can disaggregate β-amyloid plaque (WO2006/083795; U.S. Pat. No. 7,867,487; and WO2008/011503) and α-synuclein aggregates (WO2010/060073). Filamentous bacteriophage displaying protein A as a binder for antibodies and immunocomplexes to be delivered to the brain is disclosed in WO2007/095616.
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